All ETDs from UAB

Advisory Committee Chair

Kevin A Roth

Advisory Committee Members

Lalita A Shevde

Douglas Hurst

Rakesh P Patel

Yancey Gillespie

Document Type

Dissertation

Date of Award

2016

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Glioblastoma (GBM) is the most common and aggressive human primary malignant brain tumor with a 5-year survival rate of less than 5%. GBM is highly invasive, rendering complete surgical resection impossible. Additionally, this tumor type is relatively insensitive to radiotherapy. Thus, effective chemotherapeutic options present the last line of defense for GBM patients. Unfortunately, nearly 50% of all GBM tumors are resistant to the current chemotherapeutic standard, temozolomide (TMZ). TMZ is a DNA alkylating agent that promotes apoptosis via DNA damage. Resistance to TMZ-induced cell death is attributed to expression of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) resultant from hypomethylation of the mgmt promoter. MGMT mediates the removal O6-methylguanine adducts formed by TMZ, thus inhibiting the drug’s effectiveness. The overall goal of my dissertation is to identify chemotherapeutic options for GBM patients that do not rely upon induction of apoptosis. To this end, my studies focus on elucidating the mechanism(s) by which 4-hydroxy tamoxifen (OHT) mediates human GBM cell death in vitro. OHT is an active metabolite of the tamoxifen (TMX) pro-drug and a well-established Estrogen Receptor (ER) and Estrogen-Related Receptor (ERR) antagonist. This compound was chosen for investigation because it has been previously demonstrated by our lab and others to inhibit cell proliferation and promote cell death of Malignant Peripheral Nerve Sheath Tumor (MPNST) cells, another nervous system malignancy which shares glial cell lineage with GBM cells. Using both established human GBM cell lines and human GBM Patient-Derived Xenografts (PDX), my studies reveal that OHT stimulates cytotoxic autophagy and an accelerated degradation of Epidermal Growth Factor Receptor (EGFR), a key pro-survival protein in GBM. These findings demonstrate that OHT induces GBM cell death through a non-apoptotic, autophagy-related mechanism and should be investigated further to address potential utility in patient clinical trials.

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